Involvement Of Mitochondria In Diclofenac – And Ibuprofen- Induced Hepatotoxicity
Diclofenac and ibuprofen are commonly used non-steroidal anti-inflammatory drugs (NSAIDs) in the treatment of rheumatic diseases. However, these drugs are known to cause hepatotoxicity in patients. Recent in vitro studies indicated that the hepatotoxic effects of these NSAIDs are related to their...
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my-upm-ir.65562023-11-01T04:28:38Z Involvement Of Mitochondria In Diclofenac – And Ibuprofen- Induced Hepatotoxicity 2008-06 Moorthy, Mohanambal Diclofenac and ibuprofen are commonly used non-steroidal anti-inflammatory drugs (NSAIDs) in the treatment of rheumatic diseases. However, these drugs are known to cause hepatotoxicity in patients. Recent in vitro studies indicated that the hepatotoxic effects of these NSAIDs are related to their ability to induce apoptosis by targeting the mitochondria. This study was carried out to investigate and to compare possible liver perturbation following diclofenac and ibuprofen administration to rats. Male Sprague-Dawley rats (n=144) were treated with 3mg/kg, 5mg/kg and 1Omg/kg diclofenac and ibuprofen in normal saline, intraperitonealJy at 500~I/rat/day for 15 days. The control group was administered with saline in a similar manner. Four rats from each group were euthanised every 3 consecutive days. While 200mg/kg diclofenac and ibuprofen-treated rats (n=4) were euthanised following a single dose 10 hours post-treatment. Upon euthanisation, the livers were removed and cleaned with normal saline. A section across the right lobe was taken and fixed in 10% (v/v %) formal saline and 4% (v/v) glutaraldehyde for light (H&E staining and TUNEL assay) and transmission electron microscopy, respectively. The remaining samples were kept under -80°C for Western blotting analysis. The three mg/kg diclofenac administered group at day 15 showed significant presence of microvesicles and lymphocytic infiltration. The five mg/kg diclofenac-treated rats revealed significant presence of microvesicles, lymphocytic and neutrophilic infiltrations at day 15. Liver sections obtained from rats administered with 10 mg/kg diclofenac showed significant presence of microvesic1es, mild lymphocytic and neutrophilic infiltration and inflammation. The five mg/kg and 10mg/kg ibuprofeninjected rats showed significant presence of microvesicles and mild focal lymphocytic and neutrophilic infiltrations. These observations were mainly seen around central veins (CVs). In TUNEL assay, 5mg/kg and IOmg/kg diclofenac and IOmg/kg ibuprofen administered rats, showed apoptotic cells around the CVs at day 15. Ultrastructural study revealed swollen and ruptured mitochondrial membranes in rats treated with 5mg/kg diclofenac, 10mg/kg diclofenac and 10mg/kg ibuprofen on day 15. Western blotting analysis showed constant expression of cytochrome c in liver homogenate and mitochondrial fraction on day 3,6,9, 12 and 15. However no cytochrome c expression was detected in the cytosolic fraction. In 200 mg/kg diclofenac and ibuprofen-treated rats, cytochrome c was detected in all 3 fractions; homogenate, mitochondrial and cytosol. The expression of cytochrome c is higher density in the cytosol from rats administered with diclofenac when compared to the expression in cytosol from rats treated with ibuprofen. It can be concluded that diclofenac is probably more potent in inducing changes in mitochondrial membrane leading to apoptosis. However, at therapeutic dosage both drugs did not induce prominent alteration in the mitochondria and the hepatocytes in general. Drug effects 2008-06 Thesis http://psasir.upm.edu.my/id/eprint/6556/ http://psasir.upm.edu.my/id/eprint/6556/1/FPSK%28M%29_2008_1.pdf text en public masters Universiti Putra Malaysia Drug effects Faculty Medicine and Health Sciences Fakurazi, Sharida English |
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Universiti Putra Malaysia |
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English English |
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Fakurazi, Sharida |
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Drug effects |
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Drug effects Moorthy, Mohanambal Involvement Of Mitochondria In Diclofenac – And Ibuprofen- Induced Hepatotoxicity |
| description |
Diclofenac and ibuprofen are commonly used non-steroidal anti-inflammatory drugs
(NSAIDs) in the treatment of rheumatic diseases. However, these drugs are known
to cause hepatotoxicity in patients. Recent in vitro studies indicated that the
hepatotoxic effects of these NSAIDs are related to their ability to induce apoptosis
by targeting the mitochondria. This study was carried out to investigate and to
compare possible liver perturbation following diclofenac and ibuprofen
administration to rats. Male Sprague-Dawley rats (n=144) were treated with 3mg/kg,
5mg/kg and 1Omg/kg diclofenac and ibuprofen in normal saline, intraperitonealJy at
500~I/rat/day for 15 days. The control group was administered with saline in a
similar manner. Four rats from each group were euthanised every 3 consecutive
days. While 200mg/kg diclofenac and ibuprofen-treated rats (n=4) were euthanised
following a single dose 10 hours post-treatment. Upon euthanisation, the livers were
removed and cleaned with normal saline. A section across the right lobe was taken
and fixed in 10% (v/v %) formal saline and 4% (v/v) glutaraldehyde for light (H&E staining and TUNEL assay) and transmission electron microscopy, respectively. The
remaining samples were kept under -80°C for Western blotting analysis. The three
mg/kg diclofenac administered group at day 15 showed significant presence of
microvesicles and lymphocytic infiltration. The five mg/kg diclofenac-treated rats
revealed significant presence of microvesicles, lymphocytic and neutrophilic
infiltrations at day 15. Liver sections obtained from rats administered with 10 mg/kg
diclofenac showed significant presence of microvesic1es, mild lymphocytic and
neutrophilic infiltration and inflammation. The five mg/kg and 10mg/kg ibuprofeninjected
rats showed significant presence of microvesicles and mild focal
lymphocytic and neutrophilic infiltrations. These observations were mainly seen
around central veins (CVs). In TUNEL assay, 5mg/kg and IOmg/kg diclofenac and
IOmg/kg ibuprofen administered rats, showed apoptotic cells around the CVs at day
15. Ultrastructural study revealed swollen and ruptured mitochondrial membranes in
rats treated with 5mg/kg diclofenac, 10mg/kg diclofenac and 10mg/kg ibuprofen on
day 15. Western blotting analysis showed constant expression of cytochrome c in
liver homogenate and mitochondrial fraction on day 3,6,9, 12 and 15. However no
cytochrome c expression was detected in the cytosolic fraction. In 200 mg/kg
diclofenac and ibuprofen-treated rats, cytochrome c was detected in all 3 fractions;
homogenate, mitochondrial and cytosol. The expression of cytochrome c is higher
density in the cytosol from rats administered with diclofenac when compared to the
expression in cytosol from rats treated with ibuprofen. It can be concluded that
diclofenac is probably more potent in inducing changes in mitochondrial membrane
leading to apoptosis. However, at therapeutic dosage both drugs did not induce
prominent alteration in the mitochondria and the hepatocytes in general. |
| format |
Thesis |
| qualification_level |
Master's degree |
| author |
Moorthy, Mohanambal |
| author_facet |
Moorthy, Mohanambal |
| author_sort |
Moorthy, Mohanambal |
| title |
Involvement Of Mitochondria In Diclofenac – And Ibuprofen- Induced Hepatotoxicity |
| title_short |
Involvement Of Mitochondria In Diclofenac – And Ibuprofen- Induced Hepatotoxicity |
| title_full |
Involvement Of Mitochondria In Diclofenac – And Ibuprofen- Induced Hepatotoxicity |
| title_fullStr |
Involvement Of Mitochondria In Diclofenac – And Ibuprofen- Induced Hepatotoxicity |
| title_full_unstemmed |
Involvement Of Mitochondria In Diclofenac – And Ibuprofen- Induced Hepatotoxicity |
| title_sort |
involvement of mitochondria in diclofenac – and ibuprofen- induced hepatotoxicity |
| granting_institution |
Universiti Putra Malaysia |
| granting_department |
Faculty Medicine and Health Sciences |
| publishDate |
2008 |
| url |
http://psasir.upm.edu.my/id/eprint/6556/1/FPSK%28M%29_2008_1.pdf |
| _version_ |
1783725759843532800 |